Biomedicine & Pharmacotherapy 90 (2017) 935–946

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Review

Cardioprotective mechanisms of phytochemicals against

doxorubicin-induced cardiotoxicity
Abdelrahman Ibrahim Abushouka,b,1, Ammar Ismailb,c,1, Amr Muhammad Abdo Salema,b ,
Ahmed M. Afifia , Mohamed M. Abdel-Daimd,e,*
a
Faculty of Medicine, Ain Shams University, Cairo, Egypt
b
NovaMed Medical Research Association, Cairo, Egypt
c
Faculty of Medicine, Al-Azhar University, Cairo, Egypt
d
Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
e
Pharmacology Department, Dr. D.Y. Patil Medical College, Pune, Maharashtra, India

A R T I C L E I N F O A B S T R A C T

Article history:
Received 26 January 2017 Doxorubicin (DOX) is an anthracycline antibiotic, which is effectively used in the treatment of different
Received in revised form 3 April 2017 malignancies, such as leukemias and lymphomas. Its most serious side effect is dose-dependent
Accepted 10 April 2017 cardiotoxicity, which occurs through inducing oxidative stress apoptosis. Due to the myelosuppressive
effect of dexrazoxane, a commonly-used drug to alleviate DOX-induced cardiotoxicity, researchers
Keywords: investigated the potential of phytochemicals for prophylaxis and treatment of this condition.
Cardioprotection Phytochemicals are plant chemicals that have protective or disease preventive properties. Preclinical
Doxorubicin trials have shown antioxidant properties for several plant extracts, such as those of Aerva lanata, Aronia
Phytochemicals
melanocarpa, Astragalus polysaccharide, and Bombyx mori plants. Other plant extracts showed an ability to
Toxicity
inhibit apoptosis, such as those of Astragalus polysaccharide, Azadirachta indica, Bombyx mori, and Allium
stavium plants. Unlike synthetic agents, phytochemicals do not impair the clinical activity of DOX and
they are particularly safe for long-term use. In this review, we summarized the results of preclinical trials
that investigated the cardioprotective effects of phytochemicals against DOX-induced cardiotoxicity.
Future human trials are required to translate these cardioprotective mechanisms into practical clinical
implications.
© 2017 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
2. Cardiotoxic mechanisms of doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
3. Cardioprotective mechanisms of phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
3.1. Phytochemicals with antioxidant and anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
3.2. Agents with anti-apoptotic or survival-enhancing effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
3.3. Other cardioprotective mechanisms of phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
4. Implications for future clinical research and practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944

Abbreviations: ALT, alanine transferase; AST, aspartate transferase; CAT, catalase; CPK, creatine phosphokinase; DOX, doxorubicin; GSH, glutathione; GST, glutathione
transferase; LDH, lactate dehydrogenase; MDA, Malondialdehyde; ROS, reactive oxygen species; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances.
* Corresponding author.
E-mail addresses: abdeldaim.m@vet.suez.edu.eg, abdeldaim.m@gmail.com (M.M. Abdel-Daim).
1
Both authors contributed equally.

http://dx.doi.org/10.1016/j.biopha.2017.04.033
0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.
936 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946

1. Introduction superoxide (H2O2) generates peroxynitrite anion (ONOO-), known

Doxorubicin (DOX) is an anthracycline antibiotic, produced by
Streptomyces peucetius bacteria and was first used as a cytotoxic
medication in 1969 [1]. It is used in the treatment of different
malignancies e.g. leukaemia, lymphoma, and several types of
carcinomas and sarcomas [2]. Its most serious side effect is dose-
dependent cardiotoxicity [3]. Using DOX in a dose of 500–550 mg/
m2 causes cardiomyopathy in about 4% of patients, while a dose of
551–600 mg/m2 causes cardiomyopathy in about 18% of patients
and exceeding the dose of 600 mg/m2 causes cardiomyopathy in
36% of patients [4].
This cardiotoxicity can be of acute, sub-acute, or chronic onsets.
Acute cardiotoxicity occurs in about 11% of cases [5,6] and it is
manifested within 2–3 days of treatment [3]. It can be reversible
and its onset predicts the risk of heart failure in the future [7]. The
incidence of chronic cardiomyopathy is much less than acute
toxicity and is estimated to be 1.7% [8]. Although it is usually
manifested within 30 days after last dose exposure, it may not be
manifested till 6–10 years later [3]. Sub-acute and chronic
cardiotoxicity are permanent and irreversible [9]. Doxorubicin-
induced cardiotoxicity can present with any of the following
manifestations: hypotension, tachycardia, transient arrhythmias,
or late onset cardiomyopathy in the form of fatigue, dyspnea, and
lower limb edema [10].
2. Cardiotoxic mechanisms of doxorubicin
Several mechanisms were suggested for DOX-induced cardio-
toxicity, such as oxidative stress, produced by increased levels of
free radicals (e.g. reactive oxygen species (ROS) [11], and
intracellular iron [12,13]) and decreased levels of antioxidants
e.g. glutathione (GSH) [14]. This oxidative stress causes increased
intracellular calcium [14] and acceleration of lipid peroxidation
that damages the cell membrane and other cellular components
[15,16]. Moreover, DOX can stimulate inducible nitric oxide
synthase (iNOS) enzyme, increasing the production of nitric oxide
(NO), which is associated with dilated cardiomyopathy and
congestive heart failure [17]. The interaction between NO and
to cause DNA damage [18]. The highly active metabolic process and
the poorly developed antioxidant system in cardiac muscle cells
makes it more vulnerable to such toxic mechanism [19].
Doxorubicin can also induce apoptosis through two different
pathways: Intrinsic by upregulating the expression of p53 and
caspase-3 [20,21] and extrinsic by stimulating the death receptor
(Fas) and its ligand (FasL) through increased intracellular calcium
[22]. Moreover, increased ROS level suppresses the expression of
nuclear factor erythroid 2-related factor (Nrf2), which increases
the cellular susceptibility to oxidative stress and apoptosis [23].
This is detectable on the histological level in the form of
myofibrillar loss and intracellular vacuoles due to dilatation of
the sarcoplasmic reticulum (Fig. 1).
Several preclinical trials have shown that DOX can induce an
inflammatory response in the cardiac tissue through increasing the
levels of tumor necrosis factor-a (TNF-a) and inducing the
expression of neutrophil adhesion molecules on vascular endo-
thelial cells [24,25]. Arafa et al. showed that DOX treatment
induced the expression of transforming growth factor-b1 (TGF-b
1) [26], which is secreted by cardiac myofibroblasts to increase the
rate of apoptosis and cardiac fibrosis [27]. This leads to increased
collagen deposition within the ventricles and elevated levels of
fibrotic markers (e.g. Hyp content) in the cardiac tissue [26].
Myocardial fibrosis causes disturbance in impulse conductance,
reflected eletrophysiologically in the form of prolonged QT interval
[28]. Concerning vascular walls, Viero and Soares showed that DOX
treatment caused extensive fibrinoid necrosis in the walls of renal
arteries and arterioles in rats [29].
Doxorubicin can also induce cardiotoxicity by altering lipid
metabolism. Abdel-aleem et al. suggested that DOX cardiotoxicity
can be partially explained by inhibiting cardiac fatty acid oxidation,
causing energy imbalance and congestive heart failure [30]. Other
studies have shown that DOX treatment increases plasma total
cholesterol (TC), triglycerides (TAGs), and low-density lipoprotein
(LDL) levels, suggesting that DOX may interfere with the
biosynthesis (activating cyclic adenosine monophosphatase) [31]
or uptake of lipids (inhibiting lipoprotein lipase) [32].

Fig. 1. Fig. 1 shows the pathogenic effects of DOX on the molecular level and the central role of reactive oxygen species in DOX-induced cardiomyopathy.
Abbreviations: ARE: Antioxidant response element, CAT: Catalase, GPx: Glutathione Peroxidase, DOX: Doxorubicin, GR: Glutathione Reductase, ICAM-1: Intracellular
adhesion molecule-1, NADP: Nicotinamide Adenine Dinucleotide Phosphate, NF-kB: Nuclear Factor-Kappa B, Nrf: NF-E2-related factor-2, ROS: Reactive oxygen species, SOD:
Superoxide dismutase, TGF-B: Transforming growth factor B, TIMP-1: Tissue inhibitor of matrix metalloproteinase-1, VEGF: Vascular endothelial growth factor.
 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946 937

Table 1
Table 1 shows a list of phytochemical compounds and their possible anti-inflammatory and antioxidant mechanisms as shown in preclinical trials.

Phytochemical agent [Plant] Dose, route, and Animal model Doxorubicin dose and Findings and key mechanisms Reference
duration of route of administration
administration
Aged garlic extract (AGE) 250 and 500 mg/kg Male Wister 30 mg/kg, single dose, Treatment with AGE effectively prevented the Mukherjee
[Allium stavium] daily, per-oral (p.o.), for albino rats intra-peritoneal (i.p.) DOX-induced increase in thiobarbituric acid et al. [50]
30 days reactive substances (TBARS) and decrease in
endogenous antioxidants. Histopathological
examination showed that 500 mg/kg of AGE
reduced DOX-induced cardiac injury and TNF-a
expression in the myocardial cells.
(250 mg/kg for 27 days, A single dose of 25 mg/kg, Treatment with AGE enhanced the cellular Alkreathy
p.o. before DOX) i.p antioxidant defense [superoxide dismutase et al. [51] and
(SOD) and catalase (CAT) enzymes] and reduced Demirkaya
serum levels of malondialdehyde (MDA), et al. [52]
creatine phosphokinase (CPK) and lactate
dehydrogenase (LDH) enzymes.
Aloe vera (A. vera) gel [Aloe 100 mg/kg, p.o., for 10 Male Wister 7.5 mg/kg, intra-venous A. vera gel effectively increased cardiac tissue Kaithwas
barbadensis Miller] days albino rats (i.v.) on the 5th day of the level of glutathione (GSH), SOD, and CAT et al. [53,54]
experiment. enzymes. Moreover, it significantly reduced
serum levels of CPK and LDH, as well as cardiac
TBARS level.
Antarth (ANT)b 25 mg/kg, p.o., once Male Swiss 1.25 mg/kg, 24 h after the Treatment with ANT ameliorated the DOX- Jagetia et al.
daily, one hour before albino mice tumor inoculation, induced decline in cardiac tissue antioxidant [55]
DOX administration, for consecutively for 9 days. activity. Moreover, it reduced the serum levels of
9 days. alanine transferase (ALT), aspartate transferase
(AST), myocardial creatine kinase (CK-MB), and
LDH.
Aronia melanocarpa extract 20% solution of the Male and 20 mg/kg, i.p., single Treating DOX-injected animals with the extract Pavolva et al.
extract for 28 days female Balb/c injection, on the 24th day preserved cardiac tissue concentration of GSH [56]
mice of the study and the appearance of cardiomyocytes under
light microscopy.
Arjunolic acid [Terminalia 0.42, 0.85, 1.7, 3.4 and Male Wister 20 mg/kg, i.p., single dose Treatment with arjunolic acid enhanced cardiac Singh et al.
arjuna] 6.8 mg/kg, p.o., 6 days a albino rats antioxidant defence and decreased CK-MB serum [57]
week, for 4 weeks levels. It also inhibited caspase-dependent
apoptotic signalling.
Astragalus polysaccharide (1.5 g/kg) for 3 days by Neonatal rat 20 mg/kg i.p. single dose Treatment with APS ameliorated DOX-induced Cao et al. [41]
(APS) gavage before DOX and 3 cardiac cells ROS generation. Moreover, it caused profound
days after DOX. inhibition of p38 and MAPK pathways and
activation of the Akt cell survival pathway.
Avicularin and quercetin 10–80 mM for 24 h H9c2 cells 20 mM for 24 h Flavonoids from Malus hupehensis showed potent Wang et al.
flavonoids [Malus before DOX antioxidant and free radical scavenging activities, [58]
hupehensis] administration with quercetin being the most potent among
tested flavonoids.
Bombax ceiba flowers 150, 300, and 450 mg/kg, Adult male 20 mg/kg, i.p., single Treatment with BC extract/vitamin E improved Patel et al.
extract (BC) p.o., for four weeks Wister albino injection, after 4 weeks cardiac tissue antioxidant activity and reduced [59]
rats lipid peroxidation. Additionally, it decreased LDH
and AST levels in serum samples.
Bombyx mori aqueous 30 and 60 mg/kg, p.o./ Adult male 20 mg/kg, single i.p. Treatment with BMAE had a potent free radical Khan et al.
extract (BMAE) day, for 30 days wister albino injection, on 31stday scavenging activity and could reduce serum CK- [47]
rats MB and LDH levels, as well as interleukin-6
plasma level. Moreover, it suppressed the
expression of caspase-3 and TNF-a in
cardiomyocytes.
Boswellia ovalifoliolata 250 and 400 mg/kg, p.o., Male swiss 15 mg/kg, i.p., single dose, Treatment with BO extract increased the Mahesh et al.
ethanolic extract (BO) for nine days albino mice on the 7thday, in saline antioxidant activity in the cardiac tissue, [43]
reversed ECG changes caused by DOX, and
reducing serum levels of ALT, AST, LDH, and CK-
MB.
Calligonum comosum (CMC) 100 mg/kg, p.o., once Male Wister 15 mg/kg, i.p., single dose Treatment with Calligonum comosum and Cordia Ashour et al.
and Cordia myxa extracts daily, for 10 days albino rats on 7thday myxa extracts increased cardiac GSH [60]
concentration and reduced serum levels of MDA,
CK-MB, and LDH.
Calceolarioside [Calceolaria 40 mM for 30 min before H9c2 cells 1, 2, or 5 mM for 30 h Calceolarioside treatment increased the Kim et al. [61]
hypericina] DOX administration expression of antioxidant compounds (SOD, CAT,
and HO-1) and reduced the generation of ROS. It
also prevented caspase-3 activation and DOX-
induced collapse of mitochondrial membrane
potential.
Cannabidiol (CBD) 5 mg kg/day, i.p., for four Male Sprague- 2.5 mg/kg, i.p., six equal Cannabidiol significantly reduced DOX-induced Fouad et al.
[Cannabis sativa] weeks Dawley rats doses elevations of serum CK-MB and troponin-T, [62]
(Marijuana) cardiac MDA, TNF-a, NO and calcium ion levels,
and attenuated the reductions of cardiac GSH,
selenium and zinc ions. It also inhibited the
expression of NF-kB, iNOS, and caspase-3.
10 mg/kg, once daily, for Male C57BL/6J 20 mg/kg, i.p., single dose Treatment wuth CBD alleviated DOX toxicity in Hao et al. [63]
five days mice the heart by attenuating nitrative and oxidative
stress (increasing GSH and inhibiting iNOS),
938 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946

Table 1 (Continued)
Phytochemical agent [Plant] Dose, route, and Animal model Doxorubicin dose and Findings and key mechanisms Reference
duration of route of administration
administration
apoptosis (inhibiting PARP-1), as well as
increasing mitochondrial activity.
Carotenoids (Found in 50 and 100 mg/kg, p.o. Swiss albino 25 mg/kg, i.p., single dose Treatment with carotenoids demonstrated Nair et al.
different fruits and mice cardioprotection through preventing the [64]
vegetables) perioxidative damage in membrane lipids by
increasing the activity of SOD, CAT, and GPx.
Chrysoeriol [Digitalis 20 mg /ml incubation H9c2 cells – Chrysoeriol treatment protected myocytes Liu et al.[65]
purpurea] before DOX through reducing ROS generation and increasing
administration the activity of Sod and CAT.
Citrus hystrixpeels extract 500 and 1000 mg/kg, p. Female Sprague 4.67 mg/kg Treated tissue sections with ChEE showed Putri et al.
(ChEE) o. for 11 days Dawley rats regeneration of myocardial architecture and [66]
relief of DOX-induced edema; however,
numerous inflammatory cells were still present.
Cranberry [Vaccinium 100 mg/kg/day, p.o., for Male Wister 15 mg/kg, i.p., single dose, Treatment with Cranberry ameliorated the DOX- Elberry et al.
macrocarpon] 10 consecutive days albino rats on the 7thday induced elevation of LDH, CK-MB, and troponin-1 [67]
serum levels and reversed the DOX-induced ECG
changes. It prevented the reduction of cardiac
tissue levels of GSH, CAT, SOD, glutathione
reductase (GR), and glutathione peroxidase
(GPX).
Diosgenin [Dioscorea 130 mg/kg, p.o., once Male Balb/c 3 mg/kg, i.p., once a week, Diosgenin treatment decreased cardiac levels of Chen et al.
opposite] daily, for 4 weeks mice for four weeks TBARS and ROS, and prevented mitochondrial [68]
dysfunction and myocardial fibrosis. Moreover, it
reduced the expression of NF-kB and caspase-3
enzyme.
Ephedra nebrodensis alkaloid (100 mg/kg and 200 mg/ Male Wister 3 mg/kg, i.p., every other Ephedra nebrodensis extract significantly Shah et al.
extracts kg) or 100 mg/kg only, p. albino rats day, for 2 weeks increased the levels of cardiac antioxidant [69]
o., for 2 weeks. defence enzymes, such as GSH and SOD,
decreasing lipid peroxidation and serum levels of
cardiac marker enzymes.
Eugenol [Syzygium 5 mg/kg/day, p.o., for Male Sprague- 20 mg/kg, i.p., single dose Eugenol attenuated DOX-induced lipid Fouad et al.
aromaticum] seven days Dawley rats peroxidation and decreased odd Ca+2 influx into [70]
cardiomyocytes; therefore, suppressing cardiac
cell apoptosis.
Flacourtia indica (FI) 250 mg/kg and 500 mg/ Male Wister 250 and 500 mg/kg, p.o., Treatment with FI extract enhanced cardiac Palani et al.
ethanolic extract kg for 14 days. albino rats for four days tissue antioxidant defence and prevented the [71]
alteration of lipid profile parameters, such as LDL,
TAGs, and TC, as well as serum marker enzymes,
such as AST, ALT, CPK, and LDH.
Frederine. 7- 100 or 250 mg/kg, i.p., Male Wister 4 mg/kg, i.v., single dose Treatment with MonoHER2 showed dose- Acker et al.
Monohydroxyethylrutoside for
(monoHER2)
four days Albino rats dependent cardioprotective effects against DOX [72]
500 mg/kg, i.p., five toxicity, both in-vivo and in-vitro, through Acker et al.
times/week suppressing oxidative stress and apoptosis. [73,74]
Green tea extracts (GT) Total dosage: 16.3 mg/kg Male wister 1 or 2 mg/kg, i.p., once a Treatment with GT extract protected against DOX Mandziuk
(EGCG) [Camellia sinensis] b.w., per day albino rats week, for 7 weeks cardiotoxicity by improving the activity of SOD et al. [75]
enzyme, blood fatty acid-binding protein, and
brain natriuretic peptide.
3.13–200 mM infusion Sprague- 0.1, 0.5, and 1 mM for 24 h. Treatment with EGCG reduced cardaic LDH Li et al. [76]
for 1 hour. Dawley rats activity, MDA levels, and ROS production. It and Khan
increased the activity of manganese superoxide et al. [77]
dismutase (MnSOD), CAT, GPx in a dose-
dependent manner.
Globularia Alypum butanolic 100 mg/kg, p.o., for a Rats 20 mg/kg, i.p., single dose Treatment with GABE resulted in a decrease of Wahiba et al.
extract (GABE) month serum CPK, LDH, AST, and MDA levels, as well as [78]
maintenance of cardiac cytosolic GSH level.
Hemidesmus indicus root 50–100 mg/kg for 14 Adult male 25 mg/kg, as a single i.p. HiRe pre-treatment caused normalization of Zarei et al.
extract (HiRe) days Swiss albino injection serum enzyme markers including LDH, CPK, AST, [79]
mice and ALT. It also enhanced the antioxidant
machinery of cardiac tissue by increasing SOD,
CAT, and GPx activities.
Hesperidin (Citrus fruits) 50 mg/kg, p.o., for 16 Male Wister 4 mg/kg, i.p., five doses, Hesperidin works as an adjuvant to DOX, Khedr et al.
days albino mice each one every 4 days decreasing its cardiotoxicity (by increasing tissue [80]
GSH level and reducing expression of p53 and
VEGF) and synergizing its anticancer action.
25, 50 and 100 mg/kg, p. Male Sprague– 4 mg/kg, per week, for 5 Hesperidin ameliorated DOX-induced oxidative Trivedi et al.
o. by gavage, for 5 days Dawley rats weeks stress and inhibited the activation of NF-kB, [81]
caspase-3, and p38-MAPK pathways.
Hypericum hircinum extract (100 mg/kg and 200 mg/ Male Wister 3 mg/kg, i.p., every other Treatment with H. hircinum extract ameliorated Shah et al.
(H. hircinum) kg) or 100 mg/kgonly, p. albino rats day, for 2 weeks lipid peroxidation and increased cardiac tissue [82]
o., for 2 weeks. levels of GSH and SOD, and reversed ECG and
body weight changes.
Indole-3-carbinol 4 mg/kg, i.p., once BALB/c mice i.p. on days 0, 7, 14, 21 Indole-3-carbinol decreased sphingosine kinase Adwas et al.
(Cruciferous vegetables) weekly, for four weeks 1 (SphK1) activity, inhibited lipid peroxidation, [83]
and reduced serum levels of cardiotoxicity
markers.
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Table 1 (Continued)
Phytochemical agent [Plant] Dose, route, and Animal model Doxorubicin dose and Findings and key mechanisms Reference
duration of route of administration
administration
Khamira Abresham Hakim 200 mg/kg, per day, p.o., Male wister 10 mg/kg, i.v., on day 6 Treatment with GT extract increased the activites Nazmi et al.
Arshad Walaa for 7 days albino rats [2 h after saline of SOD, and CAT enzymes in cardiac tissue and [84]
administration] decreased plasma levels of MDA and LDH.
Lagenaria siceraria alcoholic 200 or 400 mg/kg, p.o., Male wister 10 mg/ kg, i.p., single dose Pretreatment with simvastatin and Lagenaria Singh et al.
seeds extrac on 29thand 30thdays of albino rats siceraria extract ameliorated cardiac lipid [85]
the study peroxidation and increased cardiac tissue levels
of antioxidants, such as CAT, SOD, and GSH.
200 mg/kg, for 18 days 10 mg/kg, i.v., on day 16 Pretreatment with Lagenaria siceraria extract was Fard et al.
associated with decreased QT and ST intervals on [86]
ECG, as well as CK-MB, LDH, and aspartate
transferase (AST) serum levels. Moreover, it
increased cardiac tissue levels of GSH and SOD.
Lipistatc 350 mg/kg, p.o., for 2 Male Wister 2.5 mg/kg, i.p., in 6 equal Lipistat reduced serum levels of LDH, MDA, CPK, Koti et al.
weeks, then 2 weeks on albino rats injections, alternatively TC, TAGs, and LDL. Moreover, it increased GSH, [87]
lipistat continuation or for 2 weeks CAT, and SOD cardiac tissue levels.
DOX.
Lycium barbarum aqueous 25 mg/kg, p.o., daily Male Sprague- 5 mg/kg, at 7, 14, and 21 Treatment with LB extract lowered mortality, Xin et al.
extract Dawley rats days prevented the loss of myofibrils, and improved [88,89]
the cardiac function. It also reversed conductive
arrhythmias and normalized cardiac antioxidant
activity, as well as serum CK and AST levels.
Lycopeneand Tomato -Lycopene: 1.7 and Male albino 15 mg/kg, i.p., single Treatment with these phytochemicals Karimi et al.
Extract 3.5 mg/kg, i.p., for four Balb/c mice injection, on the 2ndday attenuated DOX-induced myocardial [90]
days. inflammation and cellular injury, as evidenced by
-Tomato Extract: 1.2 and reduced serum levels of CK-MB.
2.4 g/kg, i.p., for four
days.
Mangiferin [Mangifera 50 and 100 mg/kg, p.o., Adult male A single injected dose of Mangiferin protected against DOX-induced Arozal et al.
indica L.] for 5 weeks Sprague- 15 mg/kg arrhythmias and decreased CPK, LDH, and MDA [91]
Dawley rats serum levels. Moreover, it showed significant
reductions in inflammatory cell number, fibrotic
area, and necrotic foci.
Morin Hydrate (Mulberry 0.17 mM incubation for ECV304 and 6 mM incubation for 12 h Morin hydrate treatment ameliorated DOX Kok et al. [49]
Bark Extract) 24 h. HepG2 cells toxicity on cardiovascular cells, such as red blood
cells, human umbilical vein endothelial cells
(ECV304), and primary mouse cardiomyocytes.
Naringenin-7-O-glucoside 10–80 mM for 24 h H9c2 cells 10 mM for 24 h Naringenin-7-O-glucoside significantly Han et al.
[Dracocephalum rupestre] before DOX enhanced cardiomyocyte proliferationand [92] and Li
administration. increased the levels of heme oxygenase-1 (HO-1) et al. [93]
and Bcl-2 in cardiomyocytes. Moreover, it
suppressed mRNA expression of caspase-3 and
caspase-9 enzymes.
5, 10, 20, 40, and 80 mM Naringenin-7-O-glucoside treatment increased Han et al.
for 24 h before DOX NAD(P)H, quinone oxidoreductase (NQO1), and [94]
administration. NF-E2-related factor-2 (Nrf2) levels in DOX-
injured myocardial cells.
Oleuropein (Oleu) 100 mg/kg, i.p., for 5 Adult male 20 mg/kg, i.p., single dose, Oleu reduced serum levels of CPK, CPK-MB, LDH, Andreadou
days Wistar rats on the 3rdday AST, ALT, as well as lipid peroxidation, protein et al. [95]
carbonyl content (PCs) content, nitro-tyrosine
(NT) concentration and iNOS induction in
myocardial tissue.
Onion [Allium cepa-ACE] 1 ml, intra-gastric (i.g.), Male Sprague– 30 mg/kg, i.p., single dose ACE-treated groups showed a significant Alpsoy et al.
extract daily, for fourteen days Dawley rats decrease in MDA levels, and increased activities [96]
of SOD, GSH and GPx in comparison with the
DOX-treated group.
Olive leaf extract (OLE)[Olea 6 and 12 mL/L, in Rats 30 mg/kg, i.p., single dose Treatment with OLE reduced serum levels of Kumral et al.
europaea] drinking water, for 12 troponin-I, urea levels, ALT, AST, MDA, diene [97]
days conjugate (DC), and protein carbonyl (PC).
Moreover, it increased cardiac GSH levels.
p-coumaric Acid [Cynodon 100 mg/kg, p.o., for five Swiss albino 15 mg/kg, i.p., single dose Pretreatment with p-coumaric acid decreased Abdel-
dactylon] days rats cardiac MDA levels and enhanced the antioxidant Wahab et al.
activity (SOD and CAT) within the cardiac tissue. [98]
Pequi oil [Caryocar An oral dose daily for 10 Female Swiss 20 mg/m2, i.v., per week Pequi oil treatment restored the normal Miranda-
brasiliense] days albino mice histopathological appearance of myocardial cells Vilela et al.
and reduced serum levels of AST, ALT, and [99]
Alkaline phosphatase (ALP).
Parkia biglobosa Methanolic 25, 50, 75 and 100 mg/ Male Wister 15 mg/kg, i.p., single Treatment with PBE lowered serum levels of Komolafe
leaf extract (PBE) kg, p.o., once daily, for 14 albino rats injection, on the 13thday MDA, CK-MB, LDH, AST, and lipid parameters. It et al. [100]
days also increased cardiac levels of GR, GPx,
glutathione s-transferase (GST).
Pomegranatewhole fruit 100 mg/kg, p.o., once Male Wistar 10 mg/kg, through the Treatment with WFEP shortened the QT interval Fard et al.
extract (WFEP) daily, for 18 days albino rats femoral vein, once, on on ECG and reduced serum levels of CK-MB, LDH, [101]
16thday and AST. It also ameliorated DOX-induced lipid
peroxidation and increased cardiac tissue GSH
level.
940 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946

Table 1 (Continued)
Phytochemical agent [Plant] Dose, route, and Animal model Doxorubicin dose and Findings and key mechanisms Reference
duration of route of administration
administration
Procyanidins from grape 150 mg/kg daily, p.o., for Male Sprague- 5 mg/kg, i.p., three times, Procyanidin treatment ameliorated myocardial Li et al. [102]
seeds 24 days Dawley rats on days 7, 14 and 21 injury and cytoplasmic vacuolization. It aslo
increased left ventricular developed pressure,
and improved ECG findings.
Resveratrol (RSVL) 20 mg/kg b.w., i.p., Healthy adult 2.5 mg/kg, i.p., six Treatment with RSVL alleviated the DOX-induced Arafa et al.
[Polygonum cuspidatum] suspended in distilled male Wister injections, over two increase in left ventricular (LV) lipid peroxidation [26]
water, for 4 weeks albino rats weeks’ period (total and TNF- a levels. It also ameliorated the up-
cumulative dose: 15 mg/kg regulation of left ventricular caspase-3,
b.w). transforming growth factor-beta1 gene
expression, and DOX-induced LV necrosis and
fibrosis.
5 mg/kg, i.p., daily for six Male Fischer 10 mg/kg, i.p., single Autophagy was induced by administering RSVL Dutta et al.
weeks (along with Brown Norway injection (50 mg/kg/day) along with 20% calorie [103]
calorie restriction). rats restriction, which contributed to protecting
cardiomyocytes from DOX-induced damage and
apoptosis.
Robinin [Vigna unguiculate] 50 mg/kg, p.o., daily, for Male Sprague 10 mg/kg, i.v., single dose Treatment with robinin inhibited lipid Janeesh et al.
10 days Dawley rats at day 7 peroxidation and reduced generation of ROS and [104]
proinflammatory mediators (by inhibiting
cyclooxygenase-II (COX2) and lipoxygenase
enzymes).
Saffron extracts [Crocus 10 mg/ml perfused Isolated rabbit 5–30 mg/ml, administered Saffron extract, perfused during electrolysis, Chahine et al.
sativus L.] through an aortic hearts during 40 min of significantly improved myocardial function and [105,106]
cannula in the coronary reperfusion. reduced oxidative myocardial damage (by ROS
circulation. trapping), associated with ischemia/reperfusion
injury.
Salsola kali aqueous extract 200 mg/kg, p.o., daily for Male Swiss 15 mg/kg, i.p., three times Pretreatment with S. kali aqueous extract Aniss et al.
three weeks albino mice over two weeks normalized serum levels of LDH, CPK, AST, and [107]
ALT. It also minimized DOX-induced lipid
peroxidation and cardiac damage.
Solanum torvum extract 100 mg/kg or 300 mg/ kg Wistar rats 67.75 mg/kg, i.v., single Treatment with S. torvum extract effectively Kamble et al.
p.o., for four weeks dose, 2 days before reversed ECG changes, decreased serum levels of [108]
sacrifice CK-MB and LDH, and increased cardiac tissue
levels of SOD and CAT.
Salvianolic Acids [Salvia 50 mg/kg, i.p. for 7 days Male Sprague- 5 mg/kg, i.p. single dose Treatment with salvianolic acids alleviated DOX- Lin et al.
miltiorrhiza] Dawley rats induced cardiotoxicity via inhibiting [109]
40 mg/kg for three days Adult male KM 15 mg/kg single i.p. dose inflammation and oxidative stress and Jiang et al.
mice preserving mitochondrial pathways. [110]
Sesamin [Sesamum indicum] 20 mg/kg, p.o., once Adult male 20 mg/kg, i.p., single dose Sesamin treatment prevented mitochondrial Su et al. [111]
daily for 10 days Sprague- on day 7 damage via activation of Sirt1, a NAD-dependent
Dawley rats class III histonedeacetylase, which increases
cellular antioxidant activity.
Sesamol [Sesamum indicum] 50 mg/kg, i.p. for 7 days. Albino Wister Total cumulative dose of Sesamol treatment alleviated lipid peroxidation, Chennuru
rats 15 mg/kg i.p. for 2 weeks in preserved cell structure, and decreased serum et al. [112]
six divided dosage leakage of cardiac enzymes. Moreover, it
improved the plasma lipid profile.
Silymarin [Silybum 100 and 200 mM for 1 h Myocytes 100 mM, added after 8 h The cardioprotective activity of silymarin can be Chlop9cíková
marianum L. Gaertneri] incubation isolated from attributed to its cell membrane stabilization, [113,114]
male Wister radical scavenging and iron chelating effects.
rats.
60 mg/kg, p.o., for 12 Adult male 1.66 mg/kg, i.p., every
Silymarin prevented DOX-induced weight loss Raškovi c
days Wistar rats other day, for 12 daysand ECG abnormalities. It also minimized the et al. [115]
perioxidative activity of DOX and its associated
cardiac damage.
Scilla hyacinthina (SHA) 250 and 500 mg/kg, p.o., Male Wister 20 mg/kg, single dose, i.p. Pretreatment with SHA significantly prevented Sakthivel
extract twice daily, for 14 days albino rats the altered biochemical variation inserum lipid et al. [116]
profile and cardiac tissue antioxidants. It also
decreased serum urea, uric acid, and ALP.
Spinach natural antioxidant cumulative dose: Female Balb/c 20 mg/kg, i.p., single dose Treatment with NAO before DOX administration Breitbart
(NAO) 130 mg/kg, i.p., 7 days mice prevented the changes in the lipid peroxidation et al. [117]
before and for 6 days product (MDA), decreased CAT and increased
after DOX treatment SOD enzyme activity, compared to DOX group.
Tetrahydroxystilbene 3–300 mM for 2 h before Neonatal rat 1 mmol/L for 24 h. Treatment with Tetrahydroxystilbene Glucoside Zhang et al.
Glucoside [Polygonum DOX administration cardiomyocytes improved cellular viability, preserved the [118]
multiflorum] histological and gross structures, and inhibited
ROS generation and caspase-3 activation.
Moreover, it upregulated the expression of Bcl-2
protein.
Thymoquinone [Nigella 8 mg/kg, daily, p.o. Mice 20 mg/kg, i.p., single dose, Thymoquinone augmented DOX activity on the Al-Shabanah
sativa Linn.] on the 5thday tumor, while protecting the heart and increasing et al.[119]
10 mg/kg/day, p.o. Adult male 15 mg/kg, i.p. its viability, as evidenced by the preserved Nagi et al.
albino rats histological structure of the heart and reductions [120]
of serum CK-MB and LDH levels.
d
Vedic Guard 270 mg/kg, daily, p.o., for Male Wistar Koti et al.
2 weeks rats [121]
 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946 941

Table 1 (Continued)
Phytochemical agent [Plant] Dose, route, and Animal model Doxorubicin dose and Findings and key mechanisms Reference
duration of route of administration
administration
2.5 mg/kg, i.p., 6 equal Vedic Guard treatment reduced serum levels of
injections, every LDH, CPK, MDA, AST, and ALT, and increased
alternative day, for 6 days cardiac tissue levels of GSH, SOD, and CAT.
Withania somnifera extract 300 mg/kg, p.o., for 14 Adult male 10 mg/kg, i.p., single dose, The extract attenuated DOX-induced damages Hamza et al.
days wistar albino after 7 days including oxidative stressand increasing [122]
rats themyeloperoxidase activity. It also reduced the
total calcium content and the expression of Bcl-2
protein in cardiomyocytes.
a
Khamira Abresham Hakim Arshad Wala is a polyherbal combination of the following plants [Carryophyllus aromaticus, Citrus aurantium, Cinnamomum iners, Crocus
sativus, Nardostachys jatamansi, Pistacia lentiscus, Punica granatum, Pyrus malus, and Bombyx mori cocoon].
b
Antarth is a poly herbal combination of the following plants [Boswellia serrata, Commiphora mukul, Withania somnifera, Smilax china, Tribulus terrestris, Tinospora cordifolia,
Curcuma longa, Alpinia galangal, Trigonella foenum-graeceum, Vitex negundo, Boerhaavia diffusa, Piper longum, Terminalia chebula, Terminalia belerica, Emblica officinalis,
Asphaltum].
c
Lipistat is a polyherbal extract of the following plants: [Terminalia arjuna, Inula racemosa, and Commiphora mukul].
d
Vedic Guard is a polyherbal combination of: Terminalia arjuna, Withania somnifera, Piper longum, Emblica officinalis, Curcuma longa, Tinosporia cordifolia, Terminalia
chebula, Glycyrrhiza glabra, Commiphora mukul, Bacopa monnieri, Sida cordifolia, Mesua ferrea, Eclipta alba, Tribulus terrestris, Pueraria tuberosa, and Asphaltum extracts.

Additional cytotoxic effects were shown in preclinical trials,
including altered calcium handling [33], impaired adrenergic
regulation through release of vasogenic amines [34], ceramide
generation [35], and inhibiting the expression of muscle-specific
genes [36]. In clinical trials of DOX in breast cancer treatment,
patients were reported to develop anemia and cardiac toxicity over
multiple cycles of chemotherapy [37].
3. Cardioprotective mechanisms of phytochemicals
Doxorubicin is a highly effective drug for the treatment of
malignancies [38]; therefore, research efforts must be directed to
prevent and treat its associated cardiotoxicity. Dexrazoxane (ICRF-
187), a drug used to reduce DOX-induced cardiotoxicity by iron
chelation, is not preferred nowadays due to its myelosuppressive
action [39]. Moreover, there is a wide debate whether it reduces
the antitumor effect of DOX. Therefore, researchers have been
trying to use phytochemicals for prevention and treatment of DOX-
induced cardiotoxicity [40–47].
Phytochemicals (Plant-derived small molecules) are non-
nutritive plant chemicals that have protective or disease
preventive properties [48]. These chemicals can be of higher
pharmaceutical values than the current drugs because they are
less expensive and easily available in natural food [49]. Preclinical
trials identified several mechanisms, underlying the observed
cardioprotective effects of phytochemicals, including antioxidant,
anti-inflammatory, and antiapoptotic mechanisms. Understand-
ing these mechanisms at the cellular and molecular levels will
help developing new prophylactic and therapeutic agents for DOX
cardiotoxicity.
3.1. Phytochemicals with antioxidant and anti-inflammatory activity
Phytochemical compounds can alleviate oxidative stress
through several pathways: 1) reducing ROS generation through
amelioration of DOX-induced lipid peroxidation, 2) performing a
potent free-radical scavenging activity, 3) enhancing the cellular
antioxidant machinery by increasing the concentration of GSH
and NADP and augmenting the activity of superoxide dismutase
(SOD), catalase (CAT), and glutathione reductase (GR) enzymes,
and 4) upregulating the expression of Nrf2, which increases heme
oxygenase-1 (HO-1) expression, and thus reducing the cellular
susceptibility to oxidative stress. Additionally, these chemicals
can exert anti-inflammatory activities including: 1) reducing the
synthesis of proinflammatory mediators by inhibiting cyclooxy-
genase-II and lipo-oxygenase enzymes, 2) downregulating the
expression of TNF-a and neutrophil adhesion molecules on
vascular endothelium, and 3) reducing collagen deposition in
inflamed tissues and amelioration of DOX-induced fibrinoid
necrosis. Several preclinical trials have shown the antioxidant and
anti-inflammatory activities of a wide array of phytochemicals
including the extracts of Aerva lanata [46], Aronia melanocarpa
[40], Astragalus polysaccharide [41], Bombyx mori [47], Boswellia
ovalifoliolata [43], Allium stavium [50], and Grape seed [45]
(Table 1).
Other plant extracts have been proven to protect against DOX
cardiotoxicity through their antioxidant properties, such as
extracts from Citrus paradise [123], Passiflora incarnata [25],
Angelica sinensis [124], Prunella vulgaris [125], Hippophae rham-
noides [126], Salvia miltiorrhiza [127], Camellia sinensis [128],
Phyllanthus urinaria [129], and Centella asiatica [130] plants.
3.2. Agents with anti-apoptotic or survival-enhancing effects
Phytochemicals, such as extracts of Astragalus polysaccharide
[41], Azadirachta indica [7], Bombyx mori [47], and Allium stavium
[20] plants can inhibit apoptosis and reduce DNA damage.
Preclinical trials listed some molecular mechanisms for the anti-
apoptotic effect of phytochemicals including: attenuating the
phosphorylation of Jun N-terminal kinase (JNK) [131], inhibiting
DOX-induced cleavage of caspases (-3, -7, -9) and poly-ADP-ribose
polymerase [132], inhibiting DOX-induced overexpression of p53
and the extracellular signal-related kinases (ERK) [125], and
increasing the levels of Akt kinase which regulates MAPK apoptotic
pathways [134] .
3.3. Other cardioprotective mechanisms of phytochemicals
1. Improving plasma lipid profile and reducing the levels of TAGs
andLDL): Barman et al. found that the extract of Urtica Parviflora
leafs (400 mg/kg daily for 3 weeks) significantly lowered plasma
levels of TAGs and LDL in DOX-intoxicated rats [148]. Similar
findings were reported with the chemical extracts of Flacourtia
indica [71], Curcuma longa [149], and lipistat polyherbal
combination [87].
2. Altering gene expression: Choi et al. found that pre-treatment of
DOX-exposed H9c2 cardiac muscle cells with 1500 mg/mL of
Schisandra fructus extract induced expression of cellular
glutathione S-transferase(GST) enzyme. Analyses of 31,100
genes, using Affymetrix cDNA microarrays, showed that SFE
treatment up-regulated the expression of genes, involved in
glutathione metabolism and detoxification [150]. Arafa et al.
942 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946

Table 2
Table 2 shows a list of phytochemical compounds and their possible anti-apoptotic mechanisms as shown in preclinical trials.

Phytochemical Dose, route, and Animal model Doxorubicin dose Findings and key mechanisms Reference
agent [Plant] duration of and route of
administration administration
Baicalein 10 mM, 24 h’ Chick 10 mM, 24 h’ Baicalein treatment attenuated DOX-induced phosphorylation of Chang et al.
[Scutellaria incubation cardiomyocyte incubation Jun N-terminal kinase (JNK) enzyme, inhibiting DOX-induced [131]
baicalensis model apoptosis. Moreover, it reduced ROS generation.
Georgi]
Clinopodium 80 mg/kg, i.g., for 15 Male Sprague- 3 mg/kg, i.p., every Treatment with TFCC suppressed DOX-induced overexpression of p Chen et al.
Chinense total days Dawley rats two days, three 53, as well as phosphorylation of JNK, p38, and the extracellular [133]
flavonoids injections totally signal-related kinases (ERK).
(TFCC)
Flavaglines (FL3) 0.1 mg/kg, i.p., At day Male BALB/cByJ 15 mg/kg, i.p., single Treatment with FL3 attenuated cardiomyocyte apoptosis and Bernard

3, 2,
1, 0 and +3 mice dose cardiac fibrosis, as reflected by a 50% decrease in mortality. et al. [135]
Glycyrrhiza 0–15 mg/L for 24 h H9c2 Rat 0.1, 0.3 and Treatment with GUE reduced p53, phospho-p53 (Ser 15), and Bax Choi et al.
uralensis before DOX Cardiac 0.5 mmol/L levels. Moreover, it inhibited DOX-induced cleavage of caspases 9, 3, [132]
extract adminstration Myoblasts 7, and poly-ADP-ribose polymerase.
(liquorice)
(GUE)
Gingerol [Zingiber 10 mg/kg, p.o., for two Male Wister 18 mg/kg, i.p., six Gingerol acts via attenuation of NF-kB activation and El-Bakly
officinalis] weeks albino rats equal doses for 2 downregulation of soluble receptor for advanced glycation end et al. [136]
weeks products.
Hydroxytyrosol 0.5 mg/kg, 5 days/ Female 1 mg/kg/week, i.v., Hydroxytyrosol treatment significantly reduced DOX-induced Granados-
[Olea europaea: week, for 6 weeks Sprague- for 6 weeks oxidative and mitochondrial damage and improved the Principal
olive oil] Dawley rats mitochondrial electron transport chain. et al. [137]
Kaempferol 1–20 mg/kg, i.p., every Male Sprague- 3 mg/kg, i.p., every Kaempferol suppressed ERK activation, with no effect on p38 and Xiao et al.
[Camellia two days, (three Dawley rats two days, three JNK. [138]
sinensis] injections) injections totally
Plantainoside D 1, 5, 10, or 20 mg/mL, H9c2 cardiac 1, 2 or 4 mM, for 30 h Acting via inhibition of ROS generation and NF-kB activation. It also Kim et al.
(PD) [Digitalis 30 min before adding muscle cells inhibited DOX-induced apoptosis of cardiac muscle cells and [139]
purpurea] DOX increased cardiac GSH levels.
Phycocyanin 10 mM incubation for Adult rat 10 mM for 4, 24, and Phycocyanin attenuated the activity of caspase-3, Bax, and Khan et al.
[Spirulina 1 h before DOX cardiomyocytes 48 h cytochrome C proteins. Moreover, it inhibited DNA fragmentation [140]
platensis) administration and ROS formation.
Osthole [Cnidium 10–40 mM incubation Neonatal rat 1 mmol for 24 h Osthole treatment suppressed myocardial apoptosis through Xu et al.
monnier] for 4 h before DOX cardiomyocytes reducing Bax, caspase-3, and cytochrome C expression. Moreover, it [141]
administration increased the cellular level of phosphorylated elF2a.
Sulforaphane 10 mM incubation for H9c2 cells 1 mM incubation for Sulforaphane treatment downregulated gene expression of Li et al.
[Brassica 2h 24 h. cytochrome C, caspase-3, and Bax proteins. Moreover, it attenuated [142]
oleracea] ROS generation and improved mitochondrial functions.
2.5 mM incubation for 5 mg/mL for 16–18 h Sulforaphane action was found to be mediated by the activation of Singh et al.
12–14 h before DOX Nrf2, the Kelch-like ECH-associated protein 1 (Keap1), and the [143]
administration antioxidant responsive element (ARE) pathway, which mediates the
initiation of HO-1.
Tetrandrine 50 mg/kg, i.p., weekly Sprague- 2 mg/kg, i.v., once a Tetrandrine improved cardiac function, improved mitochondrial Xu et al.
[Stephania Dawley rats week, for 7 weeks viability, and inhibited the rise in ROS. Furthermore, it had no effect [144]
tetrandra] 30 mg/kg, i.p. single Adult NIH mice 10 mg/kg, i.v. single on DOX pharmacokinetic profile Dai et al.
dose dose [145]
Visnagin [Ammi In-vitro incubation Neonatal rat 100 mM for 48 h Visnagin improved cardiac cell viability and mitochondrial activities Liu et al.
visnaga] with 20 mM and zebrafish (by binding to mitochondrial malate dehydrogenase enzyme) [146]
cardiac cells without affecting the DOX antitumor action
Vincristine 10–30 mM for 24 h Adult mouse 15 and 20 mg/mL for Vincristine increased cellular viability, inhibited caspase-3 and Chatterjee
[Catharanthus with DOX. cardiomyocytes 24 h PARP activities, and increased the activity of the Akt-PI3K pathway. et al. [134]
roseus]
Z-Guggulsterone 1–30 mM for 24 h after H9C2 cells 1 mM incubation for Guggulsterone preserved the cardiac cell viability and structure. It Wang et al.
[Commiphora DOX administration. 24 h decreased the activation of NF-kB, cytochrome C, caspase-3, and [147]
mukul] PARP enzymes.

reported that treatment of DOX-injected mice with 20 mg/kg of
resveratrol ameliorated gene expression of TGF-B1 [26].
3. Intracellular calcium modulation and improvement of left
ventricular (LV) contractile function: Liu et al. found that daily
treatment of DOX-intoxicated mice with 100 mg/kg of saponins
[extract of Panax notoginseng] for 5 days improved LV muscle
contraction by regulating Ca+2 influx into the myocardial cell
[151]. Similar findings were reported for saponins at lower
dosages (10–40 mg/kg) by Wang et al. [152]. In breast cancer
patients, Yi et al. found that adding Ginkgo biloba extract (EGB
761) to DOX improved left ventricular systolic diameter (LVSd),
left ventricular diastolic diameter (LVDd), ratio of early and late
diastolic transmitral peak flow velocity (E/A), and fractional
shortening (FS) [153]. Periplogenin, an extract of A. marmelos,
showed a glycoside-like action in DOX-intoxicated Wister-
albino rats, increasing intracellular Ca+2 levels and improving
myocardial contractility [154]. Other plant extracts have been
shown to reverse DOX-induced ECG changes including reducing
SR strain segment and QT interval length. These phytochemicals
include EGB-761 [155], Berberis vulgaris[156], Rhodiola rosea
(Salidroside) [157], Ixora coccinea[158], and Vaccinium myrtillus
[159].
4. Berberis vulgaris extract (at 50–200 mg/kg/day) has been
proven to ameliorate DOX cardiotoxicity by limiting its
transformation into doxorubicinol (an active metabolite) in
the cytoplasm of rat cardiac cells [160]. Fig. 2 shows the major
beneficial effects of phytochemicals against DOX-induced
cardiotoxicity.
 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946
Fig. 2. Fig. 2 summarizes the cardioprotective effects of phytochemical compounds against DOX-induced cardiotoxicity.
4. Implications for future clinical research and practice
Our review summarized the literature on the cardioprotective
effects of phytochemicals against DOX-induced Cardiotoxicity.
Many of these extracts have a dual mechanism of action, such as
antioxidant and antiapoptotic activities, giving the option to
clinicians to tackle cardiotoxicity through different pathways.
Some phytochemicals have received more attention by researchers
than others, such as aged garlic extract, resveratrol, saffron extract,
and Ginkgo biloba extract.
Our search of the literature retrieved one clinical trial in which
breast cancer patients on epirubicin were randomized to receive
either salidroside, an extract of Rhodiola rosea L. plant. The authors
concluded that salidroside reduced plasma concentrations of ROS
and prevented epirubicin-induced early LV regional systolic
dysfunction [153]. Therefore, the current evidence on the
cardioprotective effects of phytochemicals is mainly limited to
preclinical trials.
The lack of clinical trials can be referred to several reasons
including: (1) lack of evidence about the bioavailability of
phytochemicals in humans, (2) deficient knowledge about the
therapeutic indexes for most of these compounds, (3) the majority
of available studies prove the ability of phytochemicals to prevent
DOX cardiotoxicity, while in actual practice, patients usually
require treatment after the occurrence of tissue damage, and (4)
most of these studies were conducted on cellular or animal models
that are devoid of cancer cells; therefore, whether these
compounds affect the antitumor activity of doxorubicin is not
known.
There is a wide concern among oncologists that using
antioxidants may interfere with the cytotoxic mechanisms of
chemotherapeutic drugs by preventing cancer cell injury by ROS
[161]. Few studies have shown that such interference depends on
several factors, such as the type of cancer, chemotherapeutic drug,
or antioxidant, as well as the prevailing oxygen partial pressure in
the tumor [162,163]. An ideal cardioprotective agent in this regard
should not only prevent cardiotoxicity, but also should not
943
interfere with the required action of DOX. Phytochemicals, such
as thymoquinone [119] and hesperidin [80] were reported to have
a synergistic effect with the antitumor activity of DOX, while
preventing its cardiotoxicity.
To tackle these limitations, we recommend the following: (1)
Pharmaceutical companies should consider developing synthetic
derivatives of these compounds with higher bioavailability in
human tissues; (2) Future clinical trials are encouraged to use
cellular or animal models that harbor cancer cells to test the
possible interaction of phytochemicals with the antitumor activity
of DOX, (3) The promising results of preclinical trials should be
advocated and shared with cardiology and oncology clinicians, as
well as clinical methodology experts to aid in the design of high
quality clinical trials [164].
5. Conclusion
To recapitulate, phytochemicals are promising therapeutic
agents for DOX-induced cardiotoxicity. Underlying mechanisms
for these cardioprotective effects include antioxidant, antiapop-
totic, and anti-inflammatory activities. However, the current
evidence is limited to preclinical trials and limited bioavailability
in humans discourages further clinical development. To tackle this
limitation, synthetic derivatives and chemical sustained release
formulations of phytochemicals should be developed. Future trials
are required to translate these cardioprotective mechanisms into
practical clinical implications.
Funding sources
None to declare.
Conflict of interest
None to declare.
944 A.I. Abushouk et al. / Biomedicine & Pharmacotherapy 90 (2017) 935–946
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